Toxicology of the citric acid esters: Tributyl citrate, acetyl tributyl citrate, triethyl citrate, and acetyl triethyl citrate

Abstract

1. 1. Some pharmacologic and toxic properties of four citrate esters, tributyl (TBC), acetyl tributyl (ATBC), triethyl (TEC), and acetyl triethyl (ATEC) citrates, administered by the gastrointestinal route have been studied in 250 rats and 95 cats. 2. 2. The two tributyl citrates are nontoxic by the oral route in the rat and cat. They produced no local gastrointestinal irritation and no systemic effects in large single doses as high as those corresponding to more than 3 l for a man of average weight. They proved inactive also when mixed with the diet and fed for 2 months in daily amounts as high as those corresponding to 1.4 l daily for a man of average weight. This inactivity may be due to their insolubility, which may interfere with absorption. 3. 3. By comparison, the two triethyl citrates are quite potent and in most respects similar in the rat and cat. 4. 4. The oral LD 50 is approximately 7.0 cc/kg for TEC and ATEC (rat) and ATEC (cat), but only approximately 3.5 cc/kg for TEC in the cat. 5. 5. The absorption of TEC and ATEC is rapid in both species, effects appearing in a few minutes, advancing rapidly to fatality in a few hours or a day or two. When taken in the diet, large doses may be consumed daily for several weeks without toxic effects. 6. 6. Their duration of action is fairly brief, signs of poisoning subsiding in a few hours to a few days. Some of the action of these compounds remains for some time beyond the manifest effects, as shown by cumulation from repeated doses. 7. 7. Feeding these four citrate esters mixed with the diet in large daily doses for 6–8 weeks results in no deleterious effect on growth and nutrition and no effects on the blood count, hemoglobin, blood sugar, blood nitrogen, gross or histological appearance of the thoracic and abdominal organs. 8. 8. The toxic effects and the course of TEC and ATEC poisoning, studied here in greater detail in the cat, resemble those of the citrate ion introduced into the circulation, resulting in deionization of calcium and the effects of hypocalcemia.